The cardiovascular system is a common site of pathology in diabetes with pathology occurring in all of its components. Presently, much interest is directed towards an understanding of hypertension in diabetes. However, the fact remains that not all diabetics become hypertensive. Furthermore, early diabetes is associated most commonly with normotension and high microvascular perfusion, implying decreased vascular resistance during this phase of the disease. These facts, coupled with the fact that the incidence of cardiovascular complications is related to the duration of the disease underscore the need for an understanding of vascular reactivity early in diabetes. A model of chemically (streptozotocin) induced diabetes in rats has been established in which blood pressure is normal. In this model there is a depression in skeletal muscle microvascular reactivity to norepinephrine, a neurotransmitter that plays a critical role in control of blood pressure and tissue perfusion. This depression in reactivity is directly attributable to arachidonic acid metabolism since ablation of metabolism results in restoration of reactivity to norepinephrine. One component of this prostaglandin dependence is an enhanced production of prostaglandins in the diabetic. Unanswered is whether there exists also altered reactivity to the prostaglandins produced, This proposal is designed to analyze further this relation between reactivity and prostaglandins by first ascertaining whether it is present in all precapillary arterioles. Then the mechanisms underlying this relation will be explored by investigating potential loci for perturbations: receptor activation, second messengers, calcium mobilization, altered activity of enzymes of arachidonic acid metabolism, or altered reactivity to the prostaglandins being produced. In vivo studies will use topically applied drugs on the cremaster muscle thereby precluding systemic effects. In vitro studies will use monitoring in the cremaster of production of prostaglandins from exogenous and endogenous sources of substrate. Finally, studies will be initiated to improve procedures to isolate viable micro- vessels and further investigate prostaglandin metabolism. These studies should provide valuable information on how the diabetic state alters the metabolic and reactive state of the microvasculature and suggest directions for further research.